Cyclolic hydrazine derivatives as hiv attachment inhibitors

ABSTRACT

Compounds of Formula I are provided, including pharmaceutically acceptable salts thereof: wherein A is selected from the group consisting of: wherein Z is selected from the group consisting of: which are useful as HIV attachment inhibitors.

FIELD OF THE INVENTION

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Inparticular, the invention herein is directed to cyclic hydrazinederivatives as HIV attachment inhibitors that possess unique antiviralactivity.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 45 million people infected worldwide at theend of 2007. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors zidovudine (or AZT orRETROVIR®), didanosine (or VIDEX®), stavudine (or ZERIT®), lamivudine(or 3TC or EPIVIR®), zalcitabine (or DDC or HIVID®), abacavir succinate(or ZIAGEN®), tenofovir disoproxil fumarate salt (or VIREAD®),emtricitabine (or FTC-EMTRIVA®); non-nucleoside reverse transcriptaseinhibitors: nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®),efavirenz (or SUSTIVA®), etravirine (INTELENCE®) and rilpivirine(EDURANT®), and peptidomimetic protease inhibitors or approvedformulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir,lopinavir, KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir(REYATAZ®) and tipranavir (APTIVUS®), and integrase inhibitors such asraltegravir (ISENTRESS®), and entry inhibitors such as enfuvirtide(T-20) (FUZEON®) and maraviroc (SELZENTRY®). Several single pillcombinations have been also approved, which include COMBIVIR® (containslamivudine and zidovudine), TRIZIVIR® (contains abacavir, zidovudine,and lamivudine), Epzicom® (contains abacavir and lamivudine), TRUVADA®(contains tenofovir disoproxil fumarate and emtricitabine), ATRIPLA®(contains efavirenz, emtricitabine and tenofovir disoproxil fumarate)and COMPLERA® (contains emtricitabine, rilpivirine, and tenofovirdisoproxil fumarate).

Each of these drugs can only transiently restrain viral replication ifused alone. However, when used in combination, these drugs have aprofound effect on viremia and disease progression. In fact, significantreductions in death rates among AIDS patients have been documented as aconsequence of the widespread application of combination therapy.However, despite these impressive results, 30 to 50% of patients mayultimately fail combination drug therapies. Insufficient drug potency,non-compliance, restricted tissue penetration and drug-specificlimitations within certain cell types (e.g., most nucleoside analogscannot be phosphorylated in resting cells) may account for theincomplete suppression of sensitive viruses. Furthermore, the highreplication rate and rapid turnover of HIV-1 combined with the frequentincorporation of mutations, leads to the appearance of drug-resistantvariants and treatment failures when sub-optimal drug concentrations arepresent. Therefore, novel anti-HIV agents exhibiting distinct resistancepatterns, and favorable pharmacokinetic as well as safety profiles areneeded to provide more treatment options. Improved HIV fusion inhibitorsand HIV entry coreceptor antagonists are two examples of new classes ofanti-HIV agents further being studied by a number of investigators.

HIV attachment inhibitors are a novel subclass of antiviral compoundsthat bind to the HIV surface glycoprotein gp120, and interfere with theinteraction between the surface protein gp120 and the host cell receptorCD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, andblock HIV replication in the first stage of the HIV life cycle. Theproperties of HIV attachment inhibitors have been improved in an effortto obtain compounds with maximized utility and efficacy as antiviralagents. A disclosure describing indoles of which the structure shownbelow for BMS-705 is representative, has been disclosed (AntiviralIndoleoxoacetyl Piperazine Derivatives).

Two other compounds, referred to in the literature as BMS-806 andBMS-043 have been described in both the academic and patent art:

Some description of their properties in human clinical trials has beendisclosed in the literature.

It should be noted that in all three of these structures, a piperazineamide (in these three structures a piperazine phenyl amide) is presentand this group is directly attached to an oxoacetyl moiety. Theoxoacetyl group is attached at the 3-position of 4-fluoro indole inBMS-705 and to the 3 position of substituted azaindoles in BMS-806 andBMS-043.

In an effort to obtain improved anti-HIV compounds, later publicationsdescribed in part, modified substitution patterns on the indoles andazaindoles. Examples of such efforts include: (1) novel substitutedindoleoxoacetic piperazine derivatives, (2) substitutedpiperazinyloxoacetylindole derivatives, and (3) substitutedazaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteroaromatics or substitutedheteroaromatics or bicyclic hydrocarbons was also shown to be feasible.Examples include: (1) indole, azaindole and related heterocyclicamidopiperazine derivatives; (2) bicyclo[4.4.0] antiviral derivatives;and (3) diazaindole derivatives.

A select few replacements for the piperazine amide portion of themolecules have also been described in the art and among these examplesare (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) someN-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5)some carboline-containing compounds.

Method(s) for preparing prodrugs for this class of compounds aredisclosed in Prodrugs of Piperazine and Substituted Piperidine AntiviralAgents (Ueda et al., U.S. Publication No. 2005/0209246 or WO 2005/090367A1).

A published PCT patent application WO 2003/103607 A1 (Jun. 11, 2003)discloses an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies withpiperazine benzamide inhibitors, for example, U.S. Publication No.2005/0215543 (WO 2005/102328 A1), U.S. Publication No. 2005/0215544 (WO2005/102391 A1), and U.S. Publication No. 2005/0215545 (WO 2005/102392A2).

A publication on new compounds in this class of attachment inhibitors(Wang, J. et al., Org. Biol. Chem., 3:1781-1786 (2005)) and a patentapplication on some more remotely related compounds have appeared WO2005/016344 published on Feb. 24, 2005.

Published patent applications WO 2005/016344 and WO 2005/121094 alsodescribe piperazine derivatives which are HIV inhibitors. Otherreferences in the HIV attachment area include U.S. Publication Nos.2007/0155702, 2007/0078141 and 2007/0287712, WO 2007/103456, as well asU.S. Pat. Nos. 7,348,337 and 7,354,924. A literature reference is J.Med. Chem., 50:6535 (2007).

What is therefore needed in the art are new HIV attachment inhibitorcompounds, and compositions thereof, which are efficacious against HIVinfection.

Of particular interest are new cyclic hydrazine derivatives as HIVattachment inhibitor compounds, described herein. The compounds of thepresent invention are cyclic hydrazine derivatives, which are believedto be structurally distinct from the piperazine aryl amide HIVattachment inhibitors set forth in the existing literature.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I below, thepharmaceutically acceptable salts and/or solvates (e.g., hydrates)thereof, their pharmaceutical formulations, and their use in patientssuffering from or susceptible to a virus such as HIV. The compounds ofFormula I, their pharmaceutically acceptable salts and/or solvates areeffective antiviral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to a compound ofFormula I, including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

whereina, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR57, NA¹A², C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷,XR^(8a), (C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from the group F; wherein aryl is napthyl orsubstituted phenyl; wherein heteroaryl is a mono or bicyclic systemwhich contains from 3 to 7 ring atoms for a mono cyclic system and up to12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms;wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which maycontain from 1 to 2 heteroatoms in the ring skeleton and which may befused to a benzene or pyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from the groupconsisting of C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh, —C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷,SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is a monocyclic systemwhich contains from 3 to 7 ring atoms, including from 1 to 4heteroatoms;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)₂-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)₂NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)₂-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)₂-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine;R⁷ is selected from the group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic; wherein saidaryl, heteroaryl, and heteroalicyclic are optionally substituted withone to three same or different halogens or with from one to three sameor different substituents selected from the group F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of (a)hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryland (C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, hydroxyl, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO2D¹, SO2ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide and steroid, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic;Z is selected from the group consisting of:

K is selected from the group consisting of hydrogen, hydroxyl, OR^(54′),(C₁₋₆)alkyl and (C₃₋₇)cycloalkyl;I₁, I₂, I₃, I₄, I₅, and I₆ are each independently selected from thegroup consisting of H, halogen, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR₈₁R₈₂OR₈₃, COR₈₄,COOR₈₅, or CONR₈₆R₈₇; wherein each of said alkyl and cycloalkyl beingoptionally substituted with one to three same or different cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, and R₈₇ are each independently selectedfrom the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl;L is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₁₋₆)alkynyl, (C₃₋₆) cycloalkyl, halogen, cyano, CONR⁴⁰R⁴¹, S(O)₂R⁸,S(O)₂NR⁴⁰R⁴¹, C(O)R⁸, COOR⁸ tetrahydrofuryl, pyrrolidinyl, phenyl andheteroaryl; wherein said (C₁₋₆)alkyl, (C₁₋₆)alkynyl, phenyl andheteroaryl are each independently optionally substituted with one tothree same or different members selected from the group G; heteroaryl isselected from the group consisting of furanyl, thienyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;M is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are each independently optionallysubstituted with one to three same or different members selected fromthe group W; and heteroaryl is selected from the group consisting ofpyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl;W is selected from the group consisting of (C₁₋₃)alkyl, hydroxy,(C₁₋₃)alkoxy, halogen and —NR⁴²R⁴³; wherein said (C₁₋₆)alkyl isoptionally substituted with one to three same or different halogens;l, m and n are selected from the group consisting of H, halogen, OR⁸,CN, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl group and Group C; alkyl and(C₃-C₆) cycloalkyl group optionally substituted with one to threesubstitutions selected from F, OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸,SO₂N A¹A²;o and p are selected from the group consisting of H, OH, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A², (C₃-C₆) cycloalkyloptionally substituted with one to three substitutions selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A², halogen (attached tocarbon only), and Group C;q and r are selected from the group consisting of H, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A², (C₃-C₆) cycloalkyloptionally substituted with one to three substitutions (selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A² and Group C;Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group D; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl,isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl,benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl;Group C is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group D; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;Group D is selected from the group consisting of OH, OR⁸, NA¹A², CN,COOR⁸, CONA¹A², SO₂R⁸, SO₂N A¹A², (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, andwherein said alkyl or cycloalkyl group is optionally substituted withone to three substitutions selected from the group of F, OH, OR⁸, NA¹A²,COOR⁸, CONA¹A², SO₂R⁸, SO₂N A¹A²;

Another embodiment of the present invention is directed to a method fortreating mammals infected with a virus, especially wherein the virus isHIV, comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I above, and one or morepharmaceutically acceptable carriers, excipients or diluents.Optionally, the compound of Formula I can be administered in combinationwith an antiviral effective amount of an AIDS treatment agent selectedfrom the group consisting of: (a) an AIDS antiviral agent; (b) ananti-infective agent; (c) an immunomodulator; and (d) other HIV entryinhibitors.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I and one or more pharmaceutically acceptable carriers,excipients, diluents and optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or moremethods for making the compounds of Formula I.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Since the compounds of the present invention may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present disclosure includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

DEFINITIONS

Unless otherwise specifically set forth elsewhere in the application,one or more of the following terms may be used herein, and shall havethe following meanings:

The term “H” refers to hydrogen, including its isotopes.

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“C₁-C₄fluoroalkyl” refers to F-substituted C₁-C₄ alkyl wherein at leastone H atom is substituted with F atom, and each H atom can beindependently substituted by F atom.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” or “Ar” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encompass systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkylgroup may be substituted or unsubstituted. When substituted, thesubstituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroalicyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and R^(x) being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR^(Y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)NR^(X)R^(Y) group, with R^(X)and R^(Y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)(═O)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “4, 5, or 6 membered ring cyclic N-lactam” group refers to

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present disclosure are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this disclosure. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfuric acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g., hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

As stated above, the compounds of the invention also include “prodrugs”.The term “prodrug” as used herein encompasses both the term “prodrugesters” and the term “prodrug ethers”. The term “prodrug esters” asemployed herein includes esters and carbonates formed by reacting one ormore hydroxyls of compounds of Formula I with either alkyl, alkoxy, oraryl substituted acylating agents or phosphorylating agent employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, amino acid esters, phosphates,half acid esters such as malonates, succinates or glutarates, and thelike. In certain embodiments, amino acid esters may be especiallypreferred.

Examples of such prodrug esters include

The term “prodrug ethers” include both phosphate acetals andO-glucosides. Representative examples of such prodrug ethers include

Prodrug derivatives in which the prodrug moiety is attached to theindole N atom are also considered part of this invention. These prodrugscan be prepared by substitution of the indole N with a moiety thatmodifies the physical properties of the compound and can be unmaskedeither by chemical or enzymatic degradation. Examples of R₃ include acylderivatives similar to those described above. A preferred prodrug is thephosphonoxymethyl moiety which can be introduced using methodspreviously described and converted to pharmaceutically acceptable saltforms that confer chemical stability and advantageous physicalproperties:

As set forth above, the invention is directed to compounds of Formula I,including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

whereina, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A², C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷,XR^(8a), (C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from the group F; wherein aryl is napthyl orsubstituted phenyl; wherein heteroaryl is a mono or bicyclic systemwhich contains from 3 to 7 ring atoms for a mono cyclic system and up to12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms;wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which maycontain from 1 to 2 heteroatoms in the ring skeleton and which may befused to a benzene or pyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from the groupconsisting of C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh,—C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷, SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is amonocyclic system which contains from 3 to 7 ring atoms, including from1 to 4 heteroatoms;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)₂-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)₂-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine;R⁷ is selected from the group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic; wherein saidaryl, heteroaryl, and heteroalicyclic are optionally substituted withone to three same or different halogens or with from one to three sameor different substituents selected from the group F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of (a)hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryland (C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, hydroxyl, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO2D¹, SO2ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide and steroid, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic;Z is selected from the group consisting of:

K is selected from the group consisting of hydrogen, hydroxyl, OR^(54′),(C₁₋₆)alkyl and (C₃₋₇)cycloalkyl;I₁, I₂, I₃, I₄, I₅, and I₆ are each independently selected from thegroup consisting of H, halogen, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR₈₁R₈₂OR₈₃, COR₈₄,COOR₈₅, or CONR₈₆R₈₇; wherein each of said alkyl and cycloalkyl beingoptionally substituted with one to three same or different cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, and R₈₇ are each independently selectedfrom the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl;L is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₁₋₆)alkynyl, (C₃₋₆) cycloalkyl, halogen, cyano, CONR⁴⁰R⁴¹, S(O)₂R⁸,S(O)₂NR⁴⁰R⁴¹, COOR⁸, C(O)R⁸, COOR⁸, tetrahydrofuryl, pyrrolidinyl,phenyl and heteroaryl; wherein said (C₁₋₆)alkyl, (C₁₋₆)alkynyl, phenyland heteroaryl are each independently optionally substituted with one tothree same or different members selected from the group G; heteroaryl isselected from the group consisting of furanyl, thienyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;M is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are each independently optionallysubstituted with one to three same or different members selected fromthe group W; and heteroaryl is selected from the group consisting ofpyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl;W is selected from the group consisting of (C₁₋₃)alkyl, hydroxy,(C₁₋₃)alkoxy, halogen and —NR⁴²R⁴³; wherein said (C₁₋₆)alkyl isoptionally substituted with one to three same or different halogens;1, m and n are selected from the group consisting of H, halogen, OR⁸,CN, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl group and Group C; alkyl and(C₃-C₆) cycloalkyl group optionally substituted with one to threesubstitutions selected from F, OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸,SO₂N A¹A²;o and p are selected from the group consisting of H, OH, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A², (C₃-C₆) cycloalkyloptionally substituted with one to three substitutions selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A², halogen (attached tocarbon only), and Group C;q and r are selected from the group consisting of H, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A², (C₃-C₆) cycloalkyloptionally substituted with one to three substitutions (selected from F,OH, OR⁸, NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A² and Group C;Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group D; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl,isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl,benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl;Group C is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group D; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;Group D is selected from the group consisting of OH, OR⁸, NA¹A², CN,COOR⁸, CONA¹A², SO₂R⁸, SO₂N A¹A², (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, andwherein said alkyl or cycloalkyl group is optionally substituted withone to three substitutions selected from the group of F, OH, OR⁸, NA¹A²,COOR⁸, CONA¹A², SO₂R⁸, SO₂N A¹A²;

More preferred compounds of Formula I include those which are selectedfrom the group consisting of:

Of the foregoing,

are even more preferred.

The compounds of the present invention, according to all the variousembodiments described above, may be administered orally, parenterally(including subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques), by inhalation spray, orrectally, and by other means, in dosage unit formulations containingnon-toxic pharmaceutically acceptable carriers, excipients and diluentsavailable to the skilled artisan. One or more adjuvants may also beincluded.

Thus, in accordance with the present disclosure, there is furtherprovided a method of treatment, and a pharmaceutical composition, fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition which contains an antiviral effective amountof one or more of the compounds of Formula I, together with one or morepharmaceutically acceptable carriers, excipients or diluents. As usedherein, the term “antiviral effective amount” means the total amount ofeach active component of the composition and method that is sufficientto show a meaningful patient benefit, i e, inhibiting, ameliorating, orhealing of acute conditions characterized by inhibition of the HIVinfection. When applied to an individual active ingredient, administeredalone, the term refers to that ingredient alone. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the therapeutic effect, whether administeredin combination, serially or simultaneously. The terms “treat, treating,treatment” as used herein and in the claims means preventing,ameliorating or healing diseases associated with HIV infection.

The pharmaceutical compositions of the invention may be in the form oforally administrable suspensions or tablets; as well as nasal sprays,sterile injectable preparations, for example, as sterile injectableaqueous or oleaginous suspensions or suppositories. Pharmaceuticallyacceptable carriers, excipients or diluents may be utilized in thepharmaceutical compositions, and are those utilized in the art ofpharmaceutical preparations.

When administered orally as a suspension, these compositions areprepared according to techniques typically known in the art ofpharmaceutical formulation and may contain microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners/flavoringagents known in the art. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents, and lubricantsknown in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this disclosure can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses, usuallyover an extended period, such as days, weeks, months, or even years. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula Iherein set forth, together with one or more agents useful in thetreatment of AIDS. For example, the compounds of this disclosure may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of the AIDSantivirals, immunomodulators, anti-infectives, or vaccines, such asthose in the following non-limiting table:

Antivirals

Drug Name Manufacturer Indication Rilpivirine Tibotec HIV infection,AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) Complera ®Gilead HIV infection, AIDS, ARC; combination with emtricitabine,rilpivirine, and tenofovir disoproxil fumarate 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse trans- criptase (RT)inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARCAD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox BiosystemsHIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIVinfection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDSAlpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combinationw/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont(Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC NeutralizespH Concepts Labile alpha aberrant (Rockville, MD) Interferon AR177Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddA Nat'l CancerInstitute AIDS-associated diseases BMS-234475 Bristol-Myers Squibb/ HIVinfection, (CGP-61755) Novartis AIDS, ARC (protease inhibitor) CI-1012Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis,herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral CMV retinitis DarunavirTibotec-J & J HIV infection, AIDS, ARC (protease inhibitor) DelaviridinePharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan)asymptomatic ddC Hoffman-La Roche HIV infection, AIDS, DideoxycytidineARC ddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection,(DMP 266, Sustiva ®) AIDS, ARC (−)6-Chloro-4-(S)- (non-nucleoside RTcyclopropylethynyl- inhibitor) 4(S)-trifluoro- methy1-1,4-dihydro-2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Etravirine Tibotec/J & J HIV infection, AIDS, ARC(non-nucleoside reverse transcriptase inhibitor) Famciclovir Smith Klineherpes zoster, herpes simplex GS 840 Gilead HIV infection, AIDS, ARC(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection,Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human TritonBiosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCInterferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive, also in combinationwith AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC GlaxoWellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor);also with AZT Lobucavir Bristol-Myers Squibb CMV infection NelfinavirAgouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor)Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide TPeninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium AstraPharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection,other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS,ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. HIV infection, Tech (Houston, TX) AIDS, ARC RitonavirAbbott HIV infection, AIDS, ARC (protease inhibitor) SaquinavirHoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor)Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy-ARC Thymidine Tipranavir Boehringer Ingelheim HIV infection, AIDS, ARC(protease inhibitor) Valaciclovir Glaxo Wellcome Genital HSV & CMVInfections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa,CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARCZalcitabine Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZTZidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi'ssarcoma, in combination with other therapies Tenofovir disoproxil,Gilead HIV infection, fumarate salt (Viread ®) AIDS, (reversetranscriptase inhibitor) Emtriva ® (Emtricitabine) Gilead HIV infection,(FTC) AIDS, (reverse transcriptase inhibitor) Combivir ® GSK HIVinfection, AIDS, (reverse transcriptase inhibitor) Abacavir succinateGSK HIV infection, (or Ziagen ®) AIDS, (reverse transcriptase inhibitor)Reyataz ® Bristol-Myers Squibb HIV infection (or atazanavir) AIDs,protease inhibitor Fuzeon ® Roche/Trimeris HIV infection (Enfuvirtide orT-20) AIDs, viral Fusion inhibitor Lexiva ® GSK/Vertex HIV infection (orFosamprenavir calcium) AIDs, viral protease inhibitor Selzentry PfizerHIV infection Maraviroc; (UK 427857) AIDs, (CCR5 antagonist, indevelopment) Trizivir ® GSK HIV infection AIDs, (three drug combination)Sch-417690 (vicriviroc) Schering-Plough HIV infection AIDs, (CCR5antagonist, in development) TAK-652 Takeda HIV infection AIDs, (CCR5antagonist, in development) GSK 873140 GSK/ONO HIV infection (ONO-4128)AIDs, (CCR5 antagonist, in development) Integrase Inhibitor Merck HIVinfection MK-0518 AIDs Raltegravir Truvada ® Gilead Combination ofTenofovir disoproxil fumarate salt (Viread ®) and Emtriva ®(Emtricitabine) Integrase Inhibitor Gilead/Japan Tobacco HIV InfectionGS917/JTK-303 AIDs Elvitegravir in development Triple drug combinationGilead/Bristol-Myers Squibb Combination of Tenofovir Atripla ®disoproxil fumarate salt (Viread ®), Emtriva ® (Emtricitabine), andSustiva ® (Efavirenz) Festinavir ® Oncolys BioPharma HIV infection AIDsin development CMX-157 Chimerix HIV infection Lipid conjugate of AIDsnucleotide tenofovir GSK1349572 GSK HIV infection Integrase inhibitorAIDs

Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS BropiriminePharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC(Irving, TX) CL246,738 Wyeth AIDS, Kaposi's Lederle Labs sarcomaFP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells GammaInterferon Genentech ARC, in combination w/TNF (tumor necrosis factor)Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz StimulatingFactor Granulocyte Hoechst-Roussel AIDS Macrophage Colony ImmunexStimulating Factor Granulocyte Schering-Plough AIDS, Macrophage Colonycombination Stimulating Factor w/AZT HIV Core Particle RorerSeropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inInterleukin-2 CD4 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon

Immunomodulators Anti-Infectives

Drug Name Manufacturer Indication Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasisPastille Squibb Corp. Prevention of Nystatin Pastille oral candidiasisOrnidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatmentIsethionate (IM & IV) (Rosemont, IL) Trimethoprim AntibacterialTrimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Fisons Corporation PCP prophylaxis Isethionate forInhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrheaIntraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcalmeningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, SequusKaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemiaErythropoietin assoc. with AZT therapy Recombinant Human SeronoAIDS-related Growth Hormone wasting, cachexia Megestrol AcetateBristol-Myers Squibb Treatment of anorexia assoc. W/AIDS TestosteroneAlza, Smith Kline AIDS-related wasting Total Enteral Norwich EatonDiarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

Additionally, the compounds of the disclosure herein set forth may beused in combination with other HIV entry inhibitors. Examples of suchHIV entry inhibitors are discussed in Drugs of the Future,24(12):1355-1362 (1999); Cell, 9:243-246 (Oct. 29, 1999); and DrugDiscovery Today, 5(5):183-194 (May 2000) and Meanwell, N. A. et al.,“Inhibitors of the entry of HIV into host cells”, Curr. Op. Drug Disc.Dev, 6(4):451-461 (2003). Specifically the compounds can be utilized incombination with other attachment inhibitors, fusion inhibitors, andchemokine receptor antagonists aimed at either the CCR5 or CXCR4coreceptor.

It will be understood that the scope of combinations of the compounds ofthis disclosure with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable but includes, in principle, any combination with anypharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present disclosure and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is REYATAZ® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500 mgs). Anotherpreferred inhibitor of HIV protease is KALETRA®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thesecombinations may have unexpected effects on limiting the spread anddegree of infection of HIV. Preferred combinations include those withthe following (1) indinavir with efavirenz, and, optionally, AZT and/or3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddIand/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine. (The preparation ofddC, ddI and AZT are also described in EP 0 484 071.)

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Methods of Synthesis

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. The compounds may be made bymethods known in the art including those described after theAbbreviations and including variations within the skill of the art. Somereagents and intermediates are known in the art. Other reagents andintermediates can be made by methods known in the art using readilyavailable materials. The variables (e.g. numbered “R” substituents) usedto describe the synthesis of the compounds are intended only toillustrate how to make the compounds and are not to be confused withvariables used in the claims or in other sections of the specification.The following methods are for illustrative purposes and are not intendedto limit the scope of the invention.

ABBREVIATIONS

One or more of the following abbreviations, most of which areconventional abbreviations well known to those skilled in the art, maybe used throughout the description of the disclosure and the examples:

h=hour(s)rt=room temperaturemol=mole(s)mmol=millimole(s)g=gram(s)mg=milligram(s)mL=milliliter(s)TFA=trifluoroacetic Acid

DCE=1,2-Dichloroethane

CH₂Cl₂=dichloromethaneTPAP=tetrapropylammonium perruthenateTHF=tetrahydrofuranDEPBT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneDMAP=4-dimethylaminopyridineP-EDC=polymer supported 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideEDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMF=N,N-dimethylformamide Hunig's Base=N,N-diisopropylethylamine

MCPBA=meta-chloroperbenzoic acidazaindole=1H-pyrrolo-pyridine4-azaindole=1H-pyrrolo[3,2-b]pyridine5-azaindole=1H-pyrrolo[3,2-c]pyridine6-azaindole=1H-pyrrolo[2,3-c]pyridine7-azaindole=1H-pyrrolo[2,3-b]pyridinePMB=4-methoxybenzylDDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinoneOTf=trifluoromethanesulfonoxyNMM=4-methylmorpholinePIP-COPh=1-benzoylpiperazineNaHMDS=sodium hexamethyldisilazideEDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimideTMS=trimethylsilylDCM=dichloromethaneDCE=dichloroethaneMeOH=methanolTHF=tetrahydrofuranEtOAc=ethyl acetateLDA=lithium diisopropylamideTMP-Li=2,2,6,6-tetramethylpiperidinyl lithiumDME=dimethoxyethaneDIBALH=diisobutylaluminum hydrideHOBT=1-hydroxybenzotriazoleCBZ=benzyloxycarbonylPCC=pyridinium chlorochromateTBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborateDEBPT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneBOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate

Preparation of Compounds of Formula I

Preparation of template A-CO—CO—Cl and A-CO—CO—OH has been described indetail in WO-00076521, WO-0162255, WO-0204440, WO-02062423, WO-02085301,WO-03068221 and US-2004/0063744.

Standard conditions such as reacting amine with acyl halide 1 (Scheme1a) and carboxyl acid 3 (Scheme 1b) can be used to prepare the desiredamide products. Some general references of these methodologies anddirections for use are contained in “Comprehensive OrganicTransformation” by Richard C. Larock, Wiley-VCH, New York, 1989, 972(Carboxylic acids to amides), 979 (Acid halides to amides).

Scheme 1a depicts a general method for forming an amide from cyclichydrazine derivative 2 and acyl chloride 1. An appropriate base (fromcatalytic to an excess amount) selected from sodium hydride, potassiumcarbonate, triethylamine, DBU, pyridine, DMAP or di-isopropyl ethylamine was added into a solution of cyclic hydrazine 2 and acyl chloride1 in an appropriate solvent selected from dichloromethane, chloroform,benzene, toluene, THF, diethyl ether, dioxane, acetone,N,N-dimethylformamide or pyridine at room temperature. Then reaction wascarried out at either room temperature or evaluated temperature up to150° C. over a period of time (30 minutes to 48 hours) to afford thestructure of Formula I. Some selected references involving suchreactions include a) Indian J. Chem., Sect B 1990, 29, 1077; 2) Chem.Sci. 1998, 53, 1216; 3) Chem. Pharm. Bull. 1992, 40, 1481; 4) Chem.Heterocycl. Compd. 2002, 38, 539.

Alternatively, as shown in Scheme 1b, a cyclic hydrazine 2 can becoupled with an acid 3 using standard amide bond or peptide bond formingcoupling reagents. Many reagents for amide bond couplings are known byan organic chemist skilled in the art and nearly all of these areapplicable for realizing coupled amide products. The combination of EDACand triethylamine in tetrahydrofuran or BOPCl and diisopropyl ethylamine in chloroform have been utilized most frequently but DEPBT, orother coupling reagents such as PyBop could be utilized. Another usefulcoupling condition employs HATU ((a) J. Chem. Soc. Chem Comm. 1994, 201;(b) J. Am. Chem. Soc. 1994, 116, 11580). Additionally, DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, representsanother efficient method to form the amide bond and provide compounds ofFormula I. DEPBT is either purchased from Aldrich or prepared accordingto the procedure described in Organic Lett., 1999, 1, 91. Typically aninert solvent such as DMF or THF is used but other aprotic solventscould be used.

Examples

The following examples illustrate typical syntheses of the compounds ofFormula I as described generally above. These examples are illustrativeonly and are not intended to limit the disclosure in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

Chemistry Experimental Typical Procedures and Characterization ofSelected Examples:

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or VarianGemini 300 at 300 MHz as stated). The chemical shifts were reported inppm on the δ scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30), and DMSO-d6 (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

LCMS Condition: Solvent A 5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B 95% ACN: 5% Water: 10 mM Ammonium Actetate Start % B 0 Final %B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent PairACN: Water: Ammonium Actetate Column Phenomenex LUNA C18, 30 × 2, 3 u

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL)and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLCsystem.

Typical Procedures and Characterization of Selected Examples:Intermediate ACOCOOH:

Preparation of intermediate ACOCOOH was described in the previouspublished applications (T. Wang, et al. WO-2001062255 and T. Wang, etal. WO-2002062423). Some examples of ACOCOOH are listed in below.

Preparation of Intermediates Int-01 and Int-02:

Step 1:

To a stirred solution of 2-trimethylsiloxy-1,4-butadiene (10 g) in drychloroform (100 mL), (E)-di-tert-butyl diazene-1,2-dicarboxylate (12.2g) was added under nitrogen atmosphere. The reaction mixture was stirredat room temperature for 24 hours and reaction mass was concentrated. Theresulting crude was purified by column chromatography using ethylacetate\ hexane (2.0:8.0) as eluent to afford di-tert-butyl4-oxopiperazine-1,2-dicarboxylate (6 g) as yellow oil. ¹H-NMR (CDCl₃): δ1.43-1.55 (s, 18H), 2.94-3.10 (m, 2H), 3.47-3.54 (m, 1H), 3.60-3.75 (m,1H), 4.32-4.45 (m, 1H), 4.52-4.60 (m, 1H).

Step 2:

To a stirred solution of benzyl cyanide (2.5 g) in dry tetrahydrofuran(25 mL), slowly added lithium hexamethyl disilazane (26 mL, 1.0M in THF)under nitrogen atmosphere at −78° C. The reaction mixture was stirred at−78° C. for 1 hour and chloro diethyl phosphite (5 g) was added slowlyunder nitrogen atmosphere at −78° C. The reaction mixture was stirred at−78° C. for about 2 hours and quenched with saturated ammonium chloridesolution (25 mL). The reaction mixture was diluted with ethyl acetate(50 mL) and aqueous layer was extracted with ethyl acetate (2×25 mL).The combined organic layer was washed with brine (50 mL) and dried overanhydrous Na₂SO₄. Evaporation of solvent under reduced pressure gavecrude diethyl cyano(phenyl)methylphosphonate (3 g) as yellow liquid,which was used without any purification. ¹H NMR (CDCl₃): δ 1.24-1.28 (t,3H), 1.30-1.33 (t, 3H), 4.14-3.90 (m, 4H), 4.20 (d, 1H), 6 7.45-7.20 (m,5H).

Step 3:

To a solution of diethyl cyano(phenyl)methylphosphonate (10.0 g) in dryTHF (100 mL) under nitrogen, sodium bis-trimethylsilyl amide (40 mL, 1Min THF) was added dropwise at 0° C. and the resulting mixture wasstirred for 30 minutes, before di-tert-butyl4-oxopiperazine-1,2-dicarboxylate (10 g) in 25 mL of dry THF was addedin dropwise at 0° c. Reaction mixture was stirred at room temperaturefor 24 hours and the reaction was quenched with saturated ammoniumchloride (50 mL), followed by extraction with ethyl acetate (2×50 mL).The combined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to get crude product compounds Int-01 & Int-02, which wereisolated by preparative HPLC. NMR of Int-01: ¹H NMR (CDCl₃): δ 1.50-1.53(bs, 18H), 2.45-2.7 (m, 2H), 3.05-3.15 (m, 1H), 3.85-3.94 (m, 1H),4.05-4.21 (m, 1H), 5.65-5.82 (m, 1H), 7.28-7.31 (m, 2H), 7.40-7.45 (m,3H).

Synthesis of Compound 1001,(E)-2-(1-(2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-4-ylidene)-2-phenylacetonitrile

Step 1:

Int-01 (0.3 g) was dissolved in dry DCM (10 mL) and TFA (1 mL) was addedin at 0° C. The reaction mixture was stirred at room temperature for 24hours. The volatiles were completely removed under reduced pressure andthe resulting crude was diluted with dichloromethane (10 mL). Theorganic layer was washed with saturated NaHCO₃ solution (2×10 mL), brine(20 mL) and dried over Na₂SO₄. Evaporation of solvent gave(E)-2-phenyl-2-(piperazin-4-ylidene)acetonitrile (0.2 g), which was usedfurther without any purification. ¹H NMR (CDCl₃): δ 2.65-2.85 (m, 1H),2.95-3.15 (m, 1H), 3.2-3.4 (m, 1H), 3.60-3.75 (m, 1H), 4.25-4.4 (m, 1H),4.80-5.1 (m, 1H), 7.23-7.44 (m, 5H).

Step 2:

To a stirred solution of2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 mL),(E)-2-phenyl-2-(piperazin-4-ylidene)acetonitrile (80 mg), BOP reagent(240 mg) and DIPEA (0.5 mL) were added. The reaction mixture was stirredat room temperature for 24 hours and solvents was removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 mL),washed with 10% NaHCO₃ (10 mL) and brine (10 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The resulting crude waspurified by column chromatography using MeOH/CHCl₃ (0.5:9.5) as eluentto afford 1001 (50 mg) as off white solid. ¹H NMR (DMSO-d₆): δ 3.02 (m,2H), 3.42 (m, 2H), 3.90 (m, 2H), 7.30-7.50 (m, 5H), 8.13 (m, 1H), 8.30(m, 2H), 9.02 (m, 1H), 12.96 (s, 1H). LCMS: Retention time: 1.51 min/MS(M+H)⁺ Calcd. 457.1, MS (M+H)⁺ Observ. 457.3.

Synthesis of Compound 1002,(E)-2-(1-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-4-ylidene)-2-phenylacetonitrileand Compound 1003,(E)-2-(1-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)-2-methylpiperazin-4-ylidene)-2-phenylacetonitrile

Step 1:

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 mL),(E)-2-phenyl-2-(piperazin-4-ylidene)acetonitrile (80 mg), BOP reagent(218 mg) and DIPEA (0.5 mL) were added. The reaction mixture was stirredat room temperature for 24 hours and solvents was removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 mL),washed with 10% NaHCO₃ (10 mL) and brine (10 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The resulting crude waspurified by column chromatography using MeOH/CHCl₃ (0.5:9.5) as eluentto afford 1002 (50 mg) as off white solid. ¹H NMR (400 MHz, CDCl₃): δ2.45 (s, 3H), 2.49-2.53 (m, 2H), 2.96 (m, 2H), 3.87-3.91 (m, 2H), 3.93(s, 3H), 5.54 (s, 1H), 7.32-7.40 (m, 5H), 7.78 (s, 1H), 8.13 (s, 1H),9.24 (s, 1H). LCMS: Retention time: 1.43 min/MS (M+H)⁺ Calcd. 483.2, MS(M+H)⁺ Observ. 483.4.

Step 2:

To a stirred solution of 1002 (30 mg) in dry acetonitrile (5 mL), addedpotassium carbonate (18 mg) under nitrogen atmosphere at 0° C. Thereaction mixture was stirred at 0° C. for 30 minutes before methyliodide (0.05 mL) was added slowly under nitrogen atmosphere at 0° C. Thereaction mixture was stirred at room temperature for 4 hours beforebeing quenched by water (5.0 mL). Aqueous solution was extracted withethyl acetate (3×5.0 mL). The combined organic layer was washed withbrine (5.0 mL) and dried over anhydrous Na₂SO₄. Evaporation of solventunder reduced pressure gave crude product, which was purified by flashcolumn chromatography using MeOH/CHCl₃ (0.5:9.5) as eluent to afford1003 (20 mg) as off white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.53 (s,3H), 3.04-3.11 (t, 2H), 3.50 (s, 3H), 3.54-3.59 (m, 2H), 3.87-3.96 (m,2H), 4.19 (s, 3H), 7.21-7.23 (m, 2H), 7.34-7.46 (m, 3H), 7.85 (s, 1H),7.97 (s, 1H), 8.50 (s, 1H). LCMS: Retention time: 1.35 min/MS (M+H)⁺Calcd. 497.2, MS (M+H)⁺ Observ. 497.4.

Synthesis of Compound 1004,(Z)-2-(1-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-4-ylidene)-2-phenylacetonitrileand Compound 1005,(Z)-2-(2-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-4-ylidene)-2-phenylacetonitrile

Compounds 1004 and 1005 were prepared via the same process of makingcompound 1002, by using Int-02 instead of Int-01 as the startingmaterial.

NMR of 1004: ¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 2.67-2.70 (t,1H), 3.59-3.61 (d, 2H), 3.70-3.90 (m, 2H), 3.98 (s, 3H), 5.63 (m, 1H),5.80 (t, 1H), 7.37-7.39 (m, 2H), 7.44-7.51 (m, 3H), 7.86 (s, 1H), 8.20(s, 1H), 9.24 (s, 1H), 12.32 (bs, 1H). LCMS: Retention time: 1.44 min/MS(M+H)⁺ Calcd. 483.2, MS (M+H)⁺ Observ. 483.4.

NMR of 1005: ¹H NMR (400 MHz, DMSO-d₆): δ 2.47-2.48 (s, 3H), 2.66 (m,2H), 3.3 (m, 2H), 3.98 (s, 3H), 4.65 (m, 2H), 5.46-5.50 (t, 1H),7.39-7.52 (m, 5H), 7.86 (s, 1H), 8.19 (s, 1H), 9.22 (s, 1H), 12.32 (bs,1H). LCMS: Retention time: 1.46 min/MS (M+H)⁺ Calcd. 483.2, MS (M+H)⁺Observ. 483.4.

Synthesis of Compound 1006,(Z)-2-(1-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)-2-methylpiperazin-4-ylidene)-2-phenylacetonitrile

Compound 1006 was prepared via the same process of making compound 1003,by using 1004 instead of 1002 as the starting material. LCMS: Retentiontime: 1.37 min/MS (M+H)⁺ Calcd. 497.2, MS (M+H)⁺ Observ. 497.4.

Synthesis of Compound 2001,1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(1-methyl-5-phenyl-3,4-dihydropyrimido[4,5-c]pyridazin-2(1H)-yl)ethane-1,2-dione:

Step 1:

A 500 mL three necked round bottom flask was charged with diethylmalonate (20 g), dry potassium carbonate (43 g) and dry CH₃CN (200 mL)under nitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 10 minutes and allylbromide (23 g) was slowly added tothe reaction mixture at room temperature. The reaction mixture washeated to 80° C. for 24 hours. The reaction mixture was cooled to roomtemperature and filtered through celite bed. The celite bed was washedwith acetonitrile (100 mL) and the combined filtrate was concentrated togive diethyl 2-allylmalonate (24 g) as colorless liquid. ¹H NMR (CDCl₃):δ 1.26 (t, 6H), 2.61-2.67 (m, 2H), 3.42 (t, 1H), 4.20 (q, 4H), 5.03-5.16(m, 2H), 5.70-5.85 (m, 1H).

Step 2:

Sodium metal (4.5 g) was added slowly into ethanol (100 mL) in a 500 mLround bottom flask under nitrogen atmosphere. The reaction mixture wasstirred at room temperature until all the sodium metal dissolved, beforebeing cooled to 0° C. Diethyl 2-allylmalonate (12 g) was added into thereaction mixture, followed by formamidine acetate (6.24 g) undernitrogen atmosphere at 0° C. The reaction was stirred at roomtemperature for 24 hours under nitrogen atmosphere, before beingquenched by acetic acid (20 mL), followed by water (100 mL). The whiteprecipitate was filtered, washed with water (4×50 mL), methanol (2×50mL) and dried under vacuum to afford 5-allylpyrimidine-4,6-diol (4 g) aswhite solid. ¹H NMR (DMSO-d₆): δ 2.96 (d, 2H), 4.85 (dd, 1H), 4.91 (dd,1H), 5.76 (dd, 1H), 7.89 (s, 1H), 11.64 (bs, 2H).

Step 3:

A 100 ml three necked round bottom flask was charged with5-allylpyrimidine-4,6-diol (4 g) and phosphorusoxychloride (25 mL) undernitrogen atmosphere. The reaction mixture was heated to 80° C. for 3hours. The reaction mixture was cooled to room temperature and solventwas removed under reduced pressure. The resulting oil was neutralizedwith saturated NaHCO₃ solution and pH was adjusted to 8-9. The aqueouslayer was diluted with dichloromethane (100 mL) and was extracted withdichloromethane (2×50 mL). The combined organic layer was washed withbrine (50 mL) and dried over anhydrous Na₂SO₄. Evaporation of solventsunder reduced pressure gave crude compound, which was purified by columnchromatography using MeOH/CHCl₃ (0.4:9.6) as eluent to afford5-allyl-4,6-dichloropyrimidine (2.7 g). ¹H NMR (DMSO-d₆): δ 3.59-3.61(d, 2H), 5.00-5.05 (dd, 1H), 5.13-5.16 (dd, 1H), 5.85-5.94 (m, 1H), 8.8(s, 1H).

Step 4:

To a stirred solution of 5-allyl-4,6-dichloropyrimidine (2.5 g) in drydioxane (25 mL), N-methyl morpholine N-oxide (2.3 g) and osmiumtetroxide (0.85 mL, 25% solution in water) were added. The reactionmixture was stirred at room temperature for 2 hours before beingquenched by solid sodium bisulphate. The reaction mixture was filteredthrough celite bed. The celite bed was washed with dioxane (10 mL). Thecombined filtrate was taken into a 100 mL three necked round bottomflask and sodium metaperiodate (6 g, in 5 mL water) was added. Thereaction mixture was stirred at room temperature for about 3 hours, thendiluted with water (30 mL). Aqueous layer was extracted withdichloromethane (2×25 mL). The combined organic layer was washed withbrine (50 mL) and dried over anhydrous Na₂SO₄. Evaporation of solventsunder reduced pressure gave crude product, which was treated with hexaneto offer a solid. The solid obtained was filtered, washed with coldhexane (50 mL) and dried under vacuum to get2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.7 g) as white solid. ¹HNMR (DMSO-d₆): δ 4.21 (s, 2H), 8.86 (s, 1H), 9.7 (s, 1H).

Step 5:

To a stirred solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (600mg) in dry MeCN (10 mL), methyl hydrazine (154 mg) and sodium acetate(514 mg) were added. The reaction mixture was stirred at roomtemperature for 3 hours and solvents were removed under reducedpressure. The resulting oil was diluted with ethyl acetate (50 mL),washed with water (10 mL) and brine (10 mL). The organic layer was driedover anhydrous Na₂SO₄ and concentrated. The resulting crude product waspurified by column chromatography using EtOAc/CHCl₃ (0.4:9.6) as eluentto afford 5-chloro-1-methyl-1,4-dihydropyridazino[3,4-d]pyrimidine (310mg) as white solid. ¹H NMR (DMSO-d₆): δ 3.34 (s, 3H), 3.53-3.54 (d, 2H),6.91-6.93 (t, 1H), 8.38 (s, 1H).

Step 6:

The 5-chloro-1-methyl-1,4-dihydropyridazino[3,4-d]pyrimidine (310 mg),phenyl boronic acid (208 mg) and potassium carbonate (235 mg) weredissolved in toluene (10 mL) and water (1.0 mL). The reaction mixturewas degassed with nitrogen for 30 minutes and Pd(PPh₃)₄ (98 mg) wasadded. The reaction mixture was again degassed with nitrogen for 20minutes and then heated to 100° C. for 1 hour in a sealed tube. Thereaction mixture was filtered through a celite pad and washed with ethylacetate (2×20 mL). The combined filtrate was washed with water (10 mL)and brine (10 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The resulting crude product was purified by columnchromatography using MeOH/CHCl₃ (1.0:9.0) as eluent to afford1-methyl-5-phenyl-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) as offwhite solid. ¹H NMR (DMSO-d₆): δ 3.41 (s, 3H), 3.52-3.53 (d, 2H), 6.86(t, 1H), 7.47-7.49 (m, 3H), 7.56-7.60 (m, 2H), 8.66 (s, 1H).

Step 7:

To a stirred solution of1-methyl-5-phenyl-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) in drymethanol (15.0 mL), sodium borohydride (296 mg, 7.81 mmol) was addedslowly, followed by boric acid (480 mg) under nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 24 hours andsolvents were removed under reduced pressure. The resulting oil wasdiluted with dichloromethane (50 mL), washed with 10% NaHCO₃ (10 mL) andbrine (10 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated to give a residue which was purified by columnchromatography using EtOAc/hexane (1.4:8.6) as eluent to afford1-methyl-5-phenyl-1,2,3,4-tetrahydropyrimido[4,5-c]pyridazine (130 mg)as gummy liquid. ¹H NMR (DMSO-d₆): δ 2.66-2.69 (t, 2H), 2.88-2.91 (t,2H), 3.22 (s, 3H), 5.46-5.50 (t, 1H), 7.41-7.47 (m, 3H), 7.53-7.55 (m,2H), 8.36 (s, 1H).

Step 8:

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (123 mg) in dry DMF (5 mL),1-methyl-5-phenyl-1,2,3,4-tetrahydropyrimido[4,5-c]pyridazine (130 mg),BoP reagent (254 mg) and DIPEA (0.3 mL) were added. The reaction mixturewas stirred at room temperature for 24 hours and solvents were removedunder reduced pressure. The resulting oil was diluted withdichloromethane (50 mL), washed with 10% NaHCO₃ (10 mL) and brine (10mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated.The resulting residue was purified by column chromatography usingMeOH\CHCl₃ (0.2:9.8) as eluent to afford 2001 (20 mg) as off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H), 2.86-2.94 (m, 2H),3.25 (s, 3H), 3.57-3.75 (m, 1H), 3.87-3.99 (m, 1H), 4.00 (s, 3H),7.51-7.65 (m, 5H), 7.87 (s, 1H), 8.07-8.18 (m, 1H), 8.58-8.66 (m, 1H),9.12 (s, 1H), 12.10 (bs, 1H). LCMS: Retention time: 1.42 min/MS (M+H)⁺Calcd. 510.2, MS (M+H)⁺ Observ. 510.4.

Synthesis of Compound 2002,1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(1-methyl-5-(pyridin-2-yl)-3,4-dihydropyrimido[4,5-c]pyridazin-2(1H)-yl)ethane-1,2-dione

Step 1:

The 5-allyl-4,6-dichloropyrimidine (2 g) and 2-(tributylstannyl)pyridine (6.1 g) were dissolved in dry DMF (1.0 mL). The reactionmixture was degassed with nitrogen for 30 minute and Pd(PPh₃)₄ (615 mg)was added. The reaction mixture was again degassed with nitrogen for 20minutes before being irradiated under microwave at 160° C. for 30minutes. The reaction mixture was cooled to room temperature, filteredthrough a celite pad and washed with ethyl acetate (2×50 mL). Thecombined filtrate was washed with water (30 mL) and brine (30 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated. Theresulting residue was purified by column chromatography usingEtOAc/hexane (0.4:9.6) as eluent to afford5-allyl-4-chloro-6-(pyridin-2-yl)pyrimidine (1 g) as off white solid. ¹HNMR (DMSO-d₆): δ 3.80-3.82 (d, 2H), 4.83-4.89 (dd, 1H), 4.90-5.00 (dd,1H), 5.82-5.88 (m, 1H), 7.53-7.57 (m, 1H), 7.90-8.04 (m, 2H), 8.69-8.71(d, 1H), 9.0 (s, 1H).

Step 2:

To a stirred solution of 5-allyl-4-chloro-6-(pyridin-2-yl)pyrimidine (1g) in dry dioxane (10 mL), N-methyl morpholine N-oxide (0.75 g) andosmium tetroxide (0.35 mL, 25% solution in water) were added. Thereaction mixture was stirred at room temperature for 2 hours beforebeing quenched by solid sodium bisulphate. The reaction mixture wasfiltered through celite bed and the celite bed was washed with dioxane(5 mL). The combined filtrate was taken into a 100 mL three necked roundbottom flask and sodium metaperiodate (2.3 g, in 5 mL water) was added.The reaction mixture was stirred at room temperature for 3 hours andthen diluted with water (30 mL). Aqueous layer was extracted withdichloromethane (2×25 mL). The combined organic layer was washed withbrine (50 mL) and dried over anhydrous Na₂SO₄. Evaporation of solventsunder reduced pressure gave crude2-(4-chloro-6-(pyridin-2-yl)pyrimidin-5-yl)acetaldehyde (0.7 g) whichwas used as was. ¹H NMR (DMSO-d₆): δ 4.12 (s, 2H), 7.53-7.55 (m, 1H),7.88-8.01 (m, 2H), 8.66-8.69 (d, 1H), 8.97 (s, 1H), 9.79 (s, 1H).

Step 3:

To a stirred solution of2-(4-chloro-6-(pyridin-2-yl)pyrimidin-5-yl)acetaldehyde (600 mg) in dryMeCN (10 mL), methyl hydrazine (181 mg) and sodium acetate (422 mg) wereadded. The reaction mixture was stirred at room temperature for 3 hoursand solvents were removed under reduced pressure. The resulting crudewas purified by column chromatography using MeOH/CHCl₃ (0.5:9.5) aseluent to afford1-methyl-5-(pyridin-2-yl)-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg)as white solid. ¹H NMR (DMSO-d₆): δ 3.41 (s, 3H), 3.93-3.94 (d, 2H),6.92-6.94 (t, 1H), 7.47-7.51 (m, 1H), 7.94-7.99 (m, 1H), 8.00-8.10 (m,1H), 8.67-8.69 (d, 2H).

Step 4:

To a stirred solution of1-methyl-5-(pyridin-2-yl)-1,4-dihydropyrimido[4,5-c]pyridazine (100 mg)in dry THF (5.0 mL), sodium borohydride (84 mg) was slowly added,followed by boric acid (137 mg) under nitrogen atmosphere at 0° C. Thereaction mixture was stirred at room temperature for 2 hours andsolvents were removed under reduced pressure. The resulting oil wasdiluted with dichloromethane (50 mL), washed with 10% NaHCO₃ (10 mL) andbrine (10 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated to give a residue which was purified by columnchromatography using MeOH/CHCl₃ (0.5:9.5) as eluent to afford1-methyl-5-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimido[4,5-c]pyridazine(35 mg) as white solid. ¹H NMR (DMSO-d₆): δ 2.92-2.93 (m, 4H), 3.22 (s,3H), 5.49 (t, 1H), 7.41-7.44 (t, 1H), 7.90-7.92 (m, 2H), 8.38 (s, 1H),8.62-8.64 (d, 1H).

Step 5:

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (46 mg) in dry DMF (5 mL),1-methyl-5-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimido[4,5-c]pyridazine(35 mg), 2-chloro-1,3-dimethyl imidazolium chloride (54 mg) and DIPEA(0.16 mL) were added. The reaction mixture was stirred at roomtemperature for 24 hours and solvents were removed under reducedpressure. The resulting oil was diluted with dichloromethane (50 mL),washed with 10% NaHCO₃ (10 mL) and brine (10 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby column chromatography using MeOH\CHCl₃ (1.3:8.7) as eluent to afford2002 (20 mg) as white solid. ¹H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H),3.21-3.29 (m, 2H), 3.32 (s, 3H), 3.54-3.77 (m, 2H), 3.97 (s, 3H),7.44-7.52 (m, 1H), 7.82-7.86 (d, 1H), 7.93-8.03 (m, 3H), 8.58-8.66 (m,2H), 9.20 (s, 1H), 12.37 (bs, 1H). LCMS: Retention time: 1.32 min/MS(M+H)⁺ Calcd. 511.2, MS (M+H)⁺ Observ. 511.4.

Synthesis of Compound 2003,1-(1,3-dimethyl-5-phenyl-3,4-dihydropyrimido[4,5-c]pyridazin-2(1H)-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione:

Step 1:

A 500 mL two necked round bottom flask was charged with2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.2 g), dry diethyl ether(80 mL) and dry THF (80 mL). The reaction mixture was cooled to 0° C.and diazomethane solution in diethyl ether (30 mL) was slowly addedunder nitrogen atmosphere at 0° C. The reaction mixture was stirred atroom temperature for 24 hours under nitrogen atmosphere before beingquenched by acetic acid (20 mL), followed by water (100 mL). Aqueouslayer was extracted with dichloromethane (2×25 mL). The combined organiclayer was washed with brine (50 mL) and dried over anhydrous Na₂SO₄.Evaporation of solvents under reduced pressure gave crude1-(4,6-dichloropyrimidin-5-yl)propan-2-one (0.94 g) which was used aswas. ¹H NMR (DMSO-d₆): δ 2.32 (s, 3H), 4.19 (s, 2H), 8.85 (s, 1H).

Step 2:

To a stirred solution of 1-(4,6-dichloropyrimidin-5-yl)propan-2-one (940mg) in dry MeCN (10 mL), methyl hydrazine (232 mg) and sodium acetate(715 mg) were added. The reaction mixture was stirred at roomtemperature for 24 hours before being quenched with water (100 mL).Aqueous layer was extracted with dichloromethane (2×25 mL). The combinedorganic layer was washed with brine (50 mL) and dried over anhydrousNa₂SO₄. Evaporation of solvents under reduced pressure gave crude5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1 g) aswhite solid which was used as was. ¹H NMR (DMSO-d₆): δ 2.06 (s, 3H), 3.2(s, 3H), 3.55 (s, 2H), 8.33 (s, 1H).

Step 3:

The 5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1g), phenyl boronic acid (682 mg) and potassium carbonate (771 mg) weredissolved in toluene (15 mL) and water (1.5 mL). After the reactionmixture was degassed with nitrogen for 30 minute, Pd(PPh₃)₄ (323 mg) wasadded. The reaction mixture was again degassed with nitrogen for 20minutes and then heated to 100° C. for 3 hours in a sealed tube. Thereaction mixture was filtered through a celite pad and washed with ethylacetate (2×20 mL). The combined filtrate was washed with water (10 mL)and brine (10 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography usingMeOH/CHCl₃ (0.8:9.2) as eluent to afford1,3-dimethyl-5-phenyl-1,4-dihydropyridazino[3,4-d]pyrimidine (500 mg) ascolorless viscous liquid. ¹H NMR (DMSO-d₆): δ 1.89 (s, 3H), 3.37 (s,3H), 3.52 (s, 2H), 7.47-7.57 (m, 5H), 8.60 (s, 1H).

Step 4:

To a stirred solution of1,3-dimethyl-5-phenyl-1,4-dihydropyridazino[3,4-d]pyrimidine (260 mg) indry THF (15 mL), sodium borohydride (414 mg) was slowly added, followedby boric acid (670 mg) under nitrogen atmosphere at 0° C. The reactionmixture was stirred at room temperature for 2 hours and solvents wereremoved under reduced pressure. The resulting oil was diluted withdichloromethane (50 mL), washed with 10% NaHCO₃ (10 mL) and brine (10mL). The organic layer was dried over anhydrous Na₂SO₄ and concentratedto give a residue which was purified by column chromatography usingMeOH/CHCl₃ (0.5:9.5) as eluent to afford1,3-dimethyl-5-phenyl-1,2,3,4-tetrahydropyridazino[3,4-d]pyrimidine (95mg) as colorless oily liquid. ¹H NMR (DMSO-d₆): δ 1.00-1.02 (d, 3H),2.62-2.71 (t, 2H), 3.22 (s, 3H), 3.31-3.34 (m, 1H), 5.28-5.31 (d, 1H),7.43-7.51 (m, 5H), 8.36 (s, 1H).

Step 5:

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (100 mg) in dry DMF (5 mL),1,3-dimethyl-5-phenyl-1,2,3,4-tetrahydropyridazino[3,4-d]pyrimidine (80mg), 2-chloro-1,3-dimethyl imidazolium chloride (56 mg) and DIPEA (0.2mL) were added. The reaction mixture was stirred at room temperature for24 hours and solvents were removed under reduced pressure. The resultingoil was diluted with dichloromethane (50 mL), washed with 10% NaHCO₃ (10mL) and brine (10 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated. The residue was purified by column chromatographyusing MeOH\CHCl₃ (0.3:9.7) as eluent to afford 2003 (15 mg) as off whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 1.02-1.09 (m, 3H), 2.49 (s, 3H),3.36-3.37 (m, 2H), 3.56 (s, 3H), 4.00 (s, 3H), 4.35-4.41 (m, 1H),7.47-7.67 (m, 5H), 7.90 (s, 1H), 8.12 (m, 1H), 8.55 (m, 1H), 9.12 (s,1H), 12.05-12.15 (bs, 1H). LCMS: Retention time: 1.46 min/MS (M+H)⁺Calcd. 524.2, MS (M+H)⁺ Observ. 524.4.

Synthesis of Compound 2004,1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-phenyl-3,4-dihydropyrimido[4,5-c]pyridazin-2(1H)-yl)ethane-1,2-dione

Step 1:

To a stirred solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1g) in dry ethanol (10 mL), ammonium chloride (140 mg) was added. Thereaction mixture was stirred at 80° C. for 24 hours and solvents wereremoved under reduced pressure. The resulting oil was diluted withdichloromethane (50 mL), washed with 10% NaHCO₃ (20 mL) and brine (20mL). The organic layer was dried over anhydrous Na₂SO₄ and concentratedto gave crude 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (1.1 g) asviscous liquid, which was used as was. ¹H NMR (DMSO-d₆): δ 1.11-1.13 (t,6H), 2.85-2.87 (d, 2H), 3.41-3.45 (q, 4H), 4.58-4.61 (t, 1H), 9.44 (s,1H).

Step 2:

The 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (1.1 g), phenyl boronicacid (500 mg) and potassium carbonate (556 mg) were dissolved in toluene(15 mL) and water (1.5 mL). The reaction mixture was degassed withnitrogen for 30 minute and then Pd(PPh₃)₄ (230 mg) was added. Thereaction mixture was again degassed with nitrogen for 20 minutes beforeheated to 100° C. for 3 hours in a sealed tube. The reaction mixture wasfiltered through a celite pad and washed with ethyl acetate (2×20 mL).The combined filtrate was washed with water (10 mL) and brine (10 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by column chromatography using EtOAc/hexane(0.5:9.5) as eluent to afford4-chloro-5-(2,2-diethoxyethyl)-6-phenylpyrimidine (800 mg) as colorlessviscous liquid. ¹H NMR (DMSO-d₆): δ 1.07-1.10 (t, 6H), 3.21-3.23 (d,2H), 3.32-3.36 (q, 2H), 3.37-4.00 (q, 2H), 4.79-4.81 (t, 1H), 7.47-7.49(m, 3H), 7.63-7.66 (m, 2H), 8.91 (s, 1H).

Step 3:

To a stirred solution of4-chloro-5-(2,2-diethoxyethyl)-6-phenylpyrimidine (800 mg) in dry THF(10 mL), concentrated HCl (2.0 mL) was added. The reaction mixture wasstirred at 45° C. for 1 hour and solvents were removed under reducedpressure. The resulting oil was diluted with dichloromethane (50 mL),washed with 10% NaHCO₃ (20 mL) and brine (20 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby column chromatography using MeOH\CHCl₃ (0.1:9.9) as eluent to afford2-(4-chloro-6-phenylpyrimidin-5-yl)acetaldehyde (450 mg) as white solid.¹H NMR (DMSO-d₆): δ 4.04 (s, 2H), 7.42-7.53 (m, 5H), 9.02 (s, 1H), 9.72(s, 1H).

Step 4:

To a stirred solution of 2-(4-chloro-6-phenylpyrimidin-5-yl)acetaldehyde(450 mg) in dry methanol (10 mL), sodium borohydride (110 mg) was slowlyadded under nitrogen atmosphere at 0° C. The reaction mixture wasstirred at room temperature for 2 hours and solvents were removed underreduced pressure. The resulting oil was diluted with dichloromethane (50mL), washed with 10% NaHCO₃ (10 mL) and brine (10 mL). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated to give a residue whichwas purified by column chromatography using MeOH/CHCl₃ (0.2:9.8) aseluent to afford 2-(4-chloro-6-phenylpyrimidin-5-yl)ethanol (340 mg) ascolorless oily liquid. ¹H NMR (DMSO-d₆): δ 2.89-2.94 (t, 2H), 3.53-3.58(t, 2H), 4.81-4.85 (t, 1H), 7.50-7.61 (m, 5H), 8.92 (s, 1H).

Step 5:

To a stirred solution of 2-(4-chloro-6-phenylpyrimidin-5-yl)ethanol (340mg) in dry chloroform (10 mL), phosphorus oxy chloride (2 mL) was slowlyadded under nitrogen atmosphere at 0° C. The reaction mixture wasstirred at room temperature for 2 hours and solvents were removed underreduced pressure. The resulting oil was diluted with dichloromethane (50mL), washed with 10% NaHCO₃ (10 mL) and brine (10 mL). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated to gave crude4-chloro-5-(2-chloroethyl)-6-phenylpyrimidine (150 mg) as viscousliquid, which was used as was. ¹H NMR (DMSO-d₆): δ 2.89-2.94 (t, 2H),3.54-3.55 (t, 2H), 7.48-7.59 (m, 5H), 8.91 (s, 1H).

Step 6:

To a stirred solution of 4-chloro-5-(2-chloroethyl)-6-phenylpyrimidine(150 mg) in dry THF (10 mL), hydrazine (5 mL, 1.0M in THF) was slowlyadded under nitrogen atmosphere at room temperature. The reactionmixture was stirred at 60° C. for 5 hours and solvents were removedunder reduced pressure. The resulting oil was purified by columnchromatography using MeOH/CHCl₃ (0.5:9.5) as eluent to afford5-phenyl-1,2,3,4-tetrahydropyridazino[3,4-d]pyrimidine (45 mg) ascolorless oily liquid. ¹H NMR (DMSO-d₆): δ 2.63-2.65 (t, 2H), 2.79-2.81(t, 2H), 4.93-4.97 (t, 1H), 7.43-7.48 (m, 3H), 7.56-7.59 (m, 2H), 8.29(s, 1H), 8.69 (s, 1H).

Step 7:

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (56 mg) in dry DMF (5 mL),5-phenyl-1,2,3,4-tetrahydropyridazino[3,4-d]pyrimidine (40 mg), BoPreagent (79 mg) and DIPEA (0.2 mL) were added. The reaction mixture wasstirred at room temperature for 24 hours and solvents were removed underreduced pressure. The resulting oil was diluted with dichloromethane (50mL), washed with 10% NaHCO₃ (10 mL) and brine (10 mL). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column chromatography using MeOH\CHCl₃ (0.2:9.8) as eluentto afford 2004 (20 mg) as off white solid. ¹H NMR (400 MHz, DMSO-d6): δ2.45 (s, 3H), 2.88-2.92 (m, 2H), 3.59-3.65 (m, 1H), 3.77-3.89 (m, 1H),3.97 (s, 3H), 7.52-7.63 (m, 5H), 7.90 (s, 1H), 8.47-8.53 (m, 1H), 8.58(s, 1H), 9.13 (s, 1H), 12.10 (bs, 1H). LCMS: Retention time: 1.32 min/MS(M+H)⁺ Calcd. 496.2, MS (M+H)⁺ Observ. 496.4.

Biology Data for the Examples

“μM” means micromolar;

“mL” means milliliter;

“μl” means microliter;

“mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Table 1 are described below.

Cells:

-   -   Virus production—Human embryonic Kidney cell line, 293T (HEK        293T), was propagated in Dulbecco's Modified Eagle Medium        (Invitrogen, Carlsbad, Calif.) containing 10% fetal bovine serum        (FBS, Sigma, St. Louis, Mo.). The human T-cell leukemia cell MT2        (AIDS Research and Reference Reagent Program, Cat. 237) was        propagated in RPMI 1640 (Invitrogen, Carlsbad, Calif.)        containing 10% fetal bovine serum (FBS, Hyclone, Logan, Utah)    -   Virus infection—Single-round infectious reporter virus was        produced by co-transfecting HEK 293T cells with plasmide        expressing the HIV-1 LAI envelope along with a plasmid        containing an HIV-1 LAI proviral cDNA with the envelope gene        replaced by a firefly luciferase reporter gene (Chen et al., Ref        41). Transfections were performed using lipofectAMINE PLUS        reagent as described by the manufacturer (Invitrogen, Carlsbad,        Calif.).

Experimental Procedure

-   1. MT2 cells were plated in black, 384 well plates at a cell density    of 5×10³ cells per well in 25 μl RPMI 1640 containing 10% FBS.-   2. Compound (diluted in dimethylsulfoxide and growth medium) was    added to cells at 12.5 μl/well, so that the final assay    concentration would be ≦50 nM.-   3. 12.5 μl of single-round infectious reporter virus in Dulbecco's    Modified Eagle Medium was added to the plated cells and compound at    an approximate multiplicity of infection (MOI) of 0.01, resulting in    a final volume of 50 μl per well.-   4. Virus-infected cells were incubated at 37 degrees Celsius in a    CO₂ incubator and harvested 72 h after infection.-   5. Viral infection was monitored by measuring luciferase expression    in the infected cells using a luciferase reporter gene assay kit    (Steady-Glo, Promega, Madison, Wis.) as described by the    manufacturer. Luciferase activity was then quantified by measuring    luminescence using an EnVision Multilabel Plate Readers    (PerkinElmer, Waltham, Mass.).-   6. The percent inhibition for each compound was calculated by    quantifying the level of luciferase expression in cells infected in    the presence of each compound as a percentage of that observed for    cells infected in the absence of compound and subtracting such a    determined value from 100.-   7. An EC₅₀ provides a method for comparing the antiviral potency of    the compounds of this disclosure. The effective concentration for    fifty percent inhibition (EC₅₀) was calculated with the Microsoft    Excel Xlfit curve fitting software. For each compound, curves were    generated from percent inhibition calculated at 10 different    concentrations by using a four parameter logistic model (model 205).    The EC₅₀ data for the compounds is shown in Table 2. Table 1 is the    key for the data in Table 2.

TABLE 1 Biological Data Key for EC₅₀s Compounds with EC₅₀ > 0.5 μMCompounds with EC₅₀ < 0.5 μM Group B Group A

TABLE 2 EC₅₀ Compd. Group from Number Structure Table 1 1001

A 1002

A  0.29 nM 1003

A 1005

A  25.62 nM 1006

A 455.60 nM 2001

A 2002

A 2003

A 2004

A

The foregoing description is merely illustrative and should not beunderstood to limit the scope or underlying principles of the inventionin any way. Indeed, various modifications of the invention, in additionto those shown and described herein, will become apparent to thoseskilled in the art from the following examples and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims

What is claimed is:
 1. A compound of Formula I, includingpharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

wherein a, b, c, d and e are independently selected from the groupconsisting of hydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A²,C(O)R⁷, C(O)NR⁵⁵R⁵⁶, B, Q, and E; B is selected from the groupconsisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹, aryl, heteroaryl,heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷, XR^(8a),(C₁₋₆)alkylNR⁴⁰R⁴¹ (C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group F; wherein aryl is napthyl or substitutedphenyl; wherein heteroaryl is a mono or bicyclic system which containsfrom 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in afused bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is a 3 to 7 membered mono cyclic ring which may containfrom 1 to 2 heteroatoms in the ring skeleton and which may be fused to abenzene or pyridine ring; Q is selected from the group consisting of(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl and (C₂₋₆)alkenyl; wherein said(C₁₋₆)alkyl and (C₂₋₆)alkenyl are optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from the group consisting of C(O)NR⁵⁵R⁵⁶, hydroxy,cyano and XR⁵⁷; E is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and (C₂₋₆) alkenyl; wherein said (C₁₋₆)alkyl and(C₂₋₆)alkenyl are independently optionally substituted with a memberselected from the group consisting of phenyl, heteroaryl, SMe, SPh,—C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷, SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is amonocyclic system which contains from 3 to 7 ring atoms, including from1 to 4 heteroatoms; F is selected from the group consisting of(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine; R⁷ is selected from the groupconsisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, and heteroalicyclic; wherein said aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or with from one to three same or differentsubstituents selected from the group F; wherein for R⁷, R⁸, R^(8a),R^(8b) aryl is phenyl; heteroaryl is a mono or bicyclic system whichcontains from 3 to 7 ring atoms for mono cyclic systems and up to 10atoms in a bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine; R⁸ is selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl,(C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl, aryl, heteroaryl, andheteroalicyclic; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to six same ordifferent halogens or from one to five same or different substituentsselected from the group F or (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; R^(8a) is a member selected from the group consisting ofaryl, heteroaryl, and heteroalicyclic; wherein each member isindependently optionally substituted with one to six same or differenthalogens or from one to five same or different substituents selectedfrom the group F; R^(8b) is selected from the group consisting ofhydrogen, (C₁₋₆)alkyl and phenyl; X is selected from the groupconsisting of NH or NCH₃, O, and S; R⁴⁰ and R⁴¹ are independentlyselected from the group consisting of (a) hydrogen; (b) (C₁₋₆)alkyl or(C₃₋₇)cycloalkyl substituted with one to three same or differenthalogens or from one to two same or different substituents selected fromthe group F or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl, heteroaryl orheteroalicyclic; or R⁴⁰ and R⁴¹ taken together with the nitrogen towhich they are attached form a member selected from the group consistingof aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine,piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group F; wherein for R⁴⁰ and R⁴¹ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹ is notselected from groups (a) or (b); R⁴² and R⁴³ are independently selectedfrom the group consisting of hydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R⁴² and R⁴³taken together with the nitrogen to which they are attached form amember selected from the group consisting of aziridine, azetidine,pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, andmorpholine; and wherein said (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group G ordifferent functional groups: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl; heteroaryl is amonocyclic system which contains from 3 to 6 ring atoms, including from1 to 4 heteroatoms; heteroalicyclic is a member selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine; R⁴⁶ isselected from the group consisting of H, phenyl, aryl, heteroaryl and(C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶; R⁴⁷ is selected from the groupconsisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and(C₁₋₆)alkyl; R⁴⁸ and R⁴⁹ are independently selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl; R⁵⁰ isselected from the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,and benzyl; wherein each of said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl andbenzyl are optionally substituted with one to three same or different(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl R⁵⁴ is selected from the groupconsisting of hydrogen and (C₁₋₆)alkyl; R^(54′) is (C₁₋₆)alkyl; R⁵⁵ andR⁵⁶ are independently selected from the group consisting of hydrogen and(C₁₋₆)alkyl; and R⁵⁷ is selected from the group consisting of hydrogen,(C₁₋₆)alkyl, aryl, heteroaryl; and A¹ and A² are independently selectedfrom hydrogen, (C₁₋₆)alkyl, aryl, heteroaryl, SO2D¹, SO2ND²D³, COD⁴,COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶, COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure; D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ areeach independently selected from the group consisting of H, C₁-C₅₀alkyl, C₃-C₅₀ cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl,heteroaryl, C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected fromthe group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl,benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyland triazolyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₂₀ alkenyl or the carbon-carbontriple bond of said C₃-C₂₀ alkynyl are not the point of attachment tothe nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹, D¹⁰, and D¹¹ is attached;wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀ amide and C₃-C₅₀ ether isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,peroxide and steroid, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; Z is selected from the groupconsisting of:

K is selected from the group consisting of hydrogen, hydroxyl, OR^(54′),(C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; I₁, I₂, I₃, I₄, I₅, and I₆ are eachindependently selected from the group consisting of H, halogen,(C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆) alkenyl, (C₄₋₆) cycloalkenyl,(C₂₋₆) alkynyl, CR₈₁R₈₂OR₈₃, COR₈₄, COOR₈₅, or CONR₈₆R₈₇; wherein eachof said alkyl and cycloalkyl being optionally substituted with one tothree same or different cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆,and R₈₇ are each independently selected from the group consisting of H,(C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆) alkenyl, (C₄₋₆) cycloalkenyl,(C₂₋₆)alkynyl; L is selected from the group consisting of hydrogen,(C₁₋₆)alkyl, (C₁₋₆)alkynyl, (C₃₋₆) cycloalkyl, halogen, cyano,CONR⁴⁰R⁴¹, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁸, COOR⁸, tetrahydrofuryl,pyrrolidinyl, phenyl and heteroaryl; wherein said (C₁₋₆)alkyl,(C₁₋₆)alkynyl, phenyl and heteroaryl are each independently optionallysubstituted with one to three same or different members selected fromthe group G; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; M is selected fromthe group consisting of phenyl and heteroaryl; wherein said phenyl andheteroaryl are each independently optionally substituted with one tothree same or different members selected from the group W; andheteroaryl is selected from the group consisting of pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl,thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl,imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; W is selected from thegroup consisting of (C₁₋₃)alkyl, hydroxy, (C₁₋₃)alkoxy, halogen and—NR⁴²R⁴³; wherein said (C₁₋₆)alkyl is optionally substituted with one tothree same or different halogens; l, m and n are selected from the groupconsisting of H, halogen, OR⁸, CN, (C₁-C₄) alkyl, (C₃-C₆) cycloalkylgroup and Group C; alkyl and (C₃-C₆) cycloalkyl group optionallysubstituted with one to three substitutions selected from F, OH, OR⁸,NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A²; o and p are selected from thegroup consisting of H, OH, (C₁-C₄) alkyl optionally substituted with oneto three substitutions selected from F, OH, OR⁸, NA¹A², COOR⁸, CON A¹A²,SO₂R⁸, SO₂N A¹A², (C₃-C₆) cycloalkyl optionally substituted with one tothree substitutions selected from F, OH, OR⁸, NA¹A², COOR⁸, CON A¹A²,SO₂R⁸, SO₂N A¹A², halogen (attached to carbon only), and Group C; q andr are selected from the group consisting of H, (C₁-C₄) alkyl optionallysubstituted with one to three substitutions selected from F, OH, OR⁸,NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A², (C₃-C₆) cycloalkyl optionallysubstituted with one to three substitutions (selected from F, OH, OR⁸,NA¹A², COOR⁸, CON A¹A², SO₂R⁸, SO₂N A¹A² and Group C; Ar is selectedfrom the group consisting of phenyl and heteroaryl; wherein said phenyland heteroaryl are independently optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from Group D; heteroaryl is selected from thegroup consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl,benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyland triazolyl; Group C is selected from the group consisting of phenyland heteroaryl; wherein said phenyl and heteroaryl are independentlyoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from Group D;heteroaryl is selected from the group consisting of pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, andtriazolyl; Group D is selected from the group consisting of OH, OR⁸,NA¹A², CN, COOR⁸, CONA¹A², SO₂R⁸, SO₂N A¹A², (C₁-C₄) alkyl, (C₃-C₆)cycloalkyl, and wherein said alkyl or cycloalkyl group is optionallysubstituted with one to three substitutions selected from the group ofF, OH, OR^(B), NA¹A², COOR⁸, CONA¹A², SO₂R⁸, SO₂N A¹A²;
 2. A compound,including pharmaceutically acceptable salts thereof, which is selectedfrom the group consisting of:


3. The compound as claimed in claim 1, which is selected from the groupconsisting of:


4. A pharmaceutical composition which comprises an antiviral effectiveamount of one or more of the compounds of Formula I as claimed in claim2, together with one or more pharmaceutically acceptable carriers,excipients or diluents.
 5. The pharmaceutical composition of claim 4,useful for treating infection by HIV, which additionally comprises anantiviral effective amount of an AIDS treatment agent selected from thegroup consisting of: (a) an AIDS antiviral agent; (b) an anti-infectiveagent; (c) an immunomodulator; and (d) another HIV entry inhibitor.
 6. Amethod for treating a mammal infected with the HIV virus comprisingadministering to said mammal an antiviral effective amount of a compoundof Formula I as claimed in claim 2, and one or more pharmaceuticallyacceptable carriers, excipients or diluents.
 7. The method of claim 6,comprising administering to said mammal an antiviral effective amount ofa compound of Formula I, in combination with an antiviral effectiveamount of an AIDS treatment agent selected from the group consisting ofan AIDS antiviral agent; an anti-infective agent; an immunomodulator;and another HIV entry inhibitor.